PROJECT SUMMARY/ABSTRACT Memory dysfunction is a common feature in mental illnesses and neurodegenerative disease. However, treatment options for aberrant memory processes are sorely lacking, in part due to our limited understanding of the neurobiological processes that are critical for normal memory consolidation. Thus, there is an urgent need to identify molecular mechanisms regulating memory formation. The current project aims to examine mechanisms of memory consolidation within the hippocampus, a brain region critical for several different memory processes. Previous work in our lab has demonstrated that the potent estrogen 17?-estradiol (E2) can enhance memory in male and female mice when delivered systemically or directly into the dorsal hippocampus. However, whether these effects are mediated by neurons alone, or interactions between neurons and glia, remains unknown. Astrocytes, despite being the most abundant cell type in the brain, have been historically relegated to a supportive role in the central nervous system. However, recent evidence suggests a more active role for astrocytes in synaptic activity in brain regions like the hippocampus. Furthermore, astrocytes express multiple estrogen receptor subtypes, providing potential binding sites for E2 to exert its memory-enhancing effects. Our long-term goal is to pinpoint the cellular and molecular mechanisms in the hippocampus through which sex steroid hormones regulate memory formation. The overall objective for this application, which is the next step toward attainment of our goal, is to determine the extent to which astrocytes contribute to memory consolidation, and establish a potential role for astrocytes in E2's beneficial effects on memory consolidation. Our central hypotheses are that astrocytic activity at hippocampal synapses is critical for memory consolidation, and that E2-induced memory enhancement depends on astrocyte activity. These hypotheses were formulated on the basis of our own data showing that E2 enhances memory consolidation in male and female mice, data from other labs demonstrating a potential regulatory role for astrocytes in memory processes, and our preliminary data demonstrating a regulatory role for E2 in levels of astrocytic protein expression. Our hypotheses will be tested in two specific aims designed to: 1) determine the necessity of astrocytic activity in the dorsal hippocampus for memory consolidation, and 2) establish the extent to which astrocytes and E2 interact to mediate memory consolidation. This research is innovative because it represents a conceptual shift from a neuron-centric view of memory modulation. Furthermore, this research is significant because it will provide essential foundational knowledge about the ways in which astrocytes and E2 mediate memory consolidation, thereby providing sorely needed insights about memory formation that could spur development of novel therapies to reduce memory dysfunction in patients suffering from neuropsychiatric and neurodegenerative diseases.